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1. Validation of a Novel Multivariate Method of Defining HIV-Associated Cognitive Impairment

Author

Underwood, Jonathan, De Francesco, Davide, Cole, James H, Caan, Matthan W A, van Zoest, Rosan A, Schmand, Ben A, Sharp, David J, Sabin, Caroline A, Reiss, Peter, Winston, Alan Coolaboratori: Reiss P, Wit FWNM, Schouten J, Kooij KW, van Zoest RA, Elsenga BC, Janssen FR, Heidenrijk M, Zikkenheiner W, van der Valk M, Kootstra NA, Harskamp-Holwerda AM, Maurer I, Mangas Ruiz MM, Girigorie AF, Villaudy J, Frankin E, Pasternak A, Berkhout B, van der Kuyl T, Portegies P, Schmand BA, Geurtsen GJ, Ter Stege JA, Klein Twennaar M, Majoie CBLM, Caan MWA, Su T, Weijer K, Bisschop PHLT, Kalsbeek A, Wezel M, Visser I, Ruhé HG, Franceschi C, Garagnani P, Pirazzini C, Capri M, Dall'Olio F, Chiricolo M, Salvioli S, Hoeijmakers J, Pothof J, Prins M, Martens M, Moll S, Berkel J, Totté M, Kovalev S, Gisslén M, Fuchs D, Zetterberg H, Winston A, Underwood J, McDonald L, Stott M, Legg K, Lovell A, Erlwein O, Doyle N, Kingsley C, Sharp DJ, Leech R, Cole JH, Zaheri S, Hillebregt MMJ, Ruijs YMC, Benschop DP, Burger D, de Graaff-Teulen M, Guaraldi G, Bürkle A, Sindlinger T, Moreno-Villanueva M, Keller A, Sabin C, de Francesco D, Libert C, Dewaele S, Boffito M, Mallon P, Post F, Sachikonye M, Anderson J, Asboe D, Garvey L, Pozniak A, Vera J, Williams I, Campbell L, Yurdakul S, Okumu S, Pollard L, Otiko D, Phillips L, Laverick R, Fisher M, Clarke A, Bexley A, Richardson C, Macken A, Ghavani-Kia B, Maher J, Byrne M, Flaherty A, Mguni S, Clark R, Nevin-Dolan R, Pelluri S, Johnson M, Ngwu N, Hemat N, Jones M, Carroll A, Whitehouse A, Burgess L, Babalis D, Higgs C, Seah E, Fletcher S, Anthonipillai M, Moyes A, Deats K, Syed I, Matthews C., Underwood, Jonathan, De Francesco, Davide, Cole, James H, Caan, Matthan W A, van Zoest, Rosan A, Schmand, Ben A, Sharp, David J, Sabin, Caroline A, Reiss, Peter, Winston, Alan Coolaboratori: Reiss P, Wit FWNM, Schouten J, Kooij KW, van Zoest RA, Elsenga BC, Janssen FR, Heidenrijk M, Zikkenheiner W, van der Valk M, Kootstra NA, Harskamp-Holwerda AM, Maurer I, Mangas Ruiz MM, Girigorie AF, Villaudy J, Frankin E, Pasternak A, Berkhout B, van der Kuyl T, Portegies P, Schmand BA, Geurtsen GJ, Ter Stege JA, Klein Twennaar M, Majoie CBLM, Caan MWA, Su T, Weijer K, Bisschop PHLT, Kalsbeek A, Wezel M, Visser I, Ruhé HG, Franceschi C, Garagnani P, Pirazzini C, Capri M, Dall'Olio F, Chiricolo M, Salvioli S, Hoeijmakers J, Pothof J, Prins M, Martens M, Moll S, Berkel J, Totté M, Kovalev S, Gisslén M, Fuchs D, Zetterberg H, Winston A, Underwood J, McDonald L, Stott M, Legg K, Lovell A, Erlwein O, Doyle N, Kingsley C, Sharp DJ, Leech R, Cole JH, Zaheri S, Hillebregt MMJ, Ruijs YMC, Benschop DP, Burger D, de Graaff-Teulen M, Guaraldi G, Bürkle A, Sindlinger T, Moreno-Villanueva M, Keller A, Sabin C, de Francesco D, Libert C, Dewaele S, Boffito M, Mallon P, Post F, Sabin C, Sachikonye M, Winston A, Anderson J, Asboe D, Boffito M, Garvey L, Mallon P, Post F, Pozniak A, Sabin C, Sachikonye M, Vera J, Williams I, Winston A, Post F, Campbell L, Yurdakul S, Okumu S, Pollard L, Williams I, Otiko D, Phillips L, Laverick R, Fisher M, Clarke A, Vera J, Bexley A, Richardson C, Mallon P, Macken A, Ghavani-Kia B, Maher J, Byrne M, Flaherty A, Anderson J, Mguni S, Clark R, Nevin-Dolan R, Pelluri S, Johnson M, Ngwu N, Hemat N, Jones M, Carroll A, Whitehouse A, Burgess L, Babalis D, Winston A, Garvey L, Underwood J, Stott M, McDonald L, Boffito M, Asboe D, Pozniak A, Higgs C, Seah E, Fletcher S, Anthonipillai M, Moyes A, Deats K, Syed I, Matthews C., Molecular Genetics, Biomedical Engineering and Physics, Radiology and Nuclear Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, ACS - Microcirculation, AMS - Restoration & Development, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Neurovascular Disorders, Graduate School, AII - Infectious diseases, APH - Aging & Later Life, Medical Psychology, Amsterdam Neuroscience - Neurodegeneration, Global Health, Infectious diseases, APH - Mental Health, APH - Methodology, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, and National Institute for Health Research

Subjects
Multivariate statistics, medicine.medical_specialty, COmorBidity in Relation to AIDS (COBRA) Collaboration and the Pharmacokinetic and clinical Observations in PePle over fiftY (POPPY) Study Group, Immunology, Human immunodeficiency virus (HIV), Audiology, medicine.disease_cause, Microbiology, 03 medical and health sciences, 0302 clinical medicine, multivariate, SDG 3 - Good Health and Well-being, Neuroimaging, Medicine and Health Sciences, medicine, Major Article, OLDER-PEOPLE, 030212 general & internal medicine, VALIDITY, Cognitive impairment, cognitive impairment, Science & Technology, neuroimaging, SCORES, business.industry, Biology and Life Sciences, HIV, MEN, Cognition, Mental health, White matter microstructure, PREVALENCE, 3. Good health, Infectious Diseases, Oncology, REGISTRATION, business, Life Sciences & Biomedicine, Neurocognitive, 030217 neurology & neurosurgery
Abstract

Background The optimum method of defining cognitive impairment in virally suppressed people living with HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patient– reported outcome measures (PROMs), and neuroimaging markers of brain structure across 3 cohorts. Methods Differences in the prevalence of cognitive impairment, PROMs, and neuroimaging data from the COBRA, CHARTER, and POPPY cohorts (total n = 908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS), and NMM criteria. Results The prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (eg, 48% for HAND vs 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints generally were weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment (P < .05). There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres (P < .05), as well as smaller brain volumes (P < .01). The associations with measures of white matter microstructure and brain-predicted age generally were weaker. Conclusion Different methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer self-reported health status. This may be due to the statistical advantage of using a multivariate approach., We have previously described a novel multivariate method (NMM) with theoretical statistical advantages over existing methods, which we assessed here in 3 cohorts of people living with HIV. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer self-reported health status.

Published
2019

2. New or Progressive Multiple Organ Dysfunction Syndrome in Pediatric Severe Sepsis: A Sepsis Phenotype With Higher Morbidity and Mortality

Author

Lin, John C, Spinella, Philip C., Fitzgerald, Julie C., Tucci, Marisa, Bush, Jenny L., Nadkarni, Vinay M., Thomas, Neal J., Weiss, Scott L., Fontela, P., Tucci, M., Dumistrascu, M., Skippen, P., Krahn, G., Bezares, E., Puig, G., Puig Ramos, A., Garcia, R., Villar, M., Bigham, M., Polanski, T., Latifi, S., Giebner, D., Anthony, H., Hume, J., Galster, A., Linnerud, L., Sanders, R., Hefley, G., Madden, K., Thompson, A., Shein, S., Gertz, S., Han, Y., Williams, T., Hughes Schalk, A., Chandler, H., Orioles, A., Zielinski, E., Doucette, A., Zebuhr, C., Wilson, T., Dimitriades, C., Ascani, J., Layburn, S., Valley, S., Markowitz, B., Terry, J., Morzov, R., Mcinnes, A., Mcarthur, J., Woods, K., Murkowski, K., Spaeder, M., Sharron, M., Wheeler, D., Beckman, E., Frank, E., Howard, K., Carroll, C., Nett, S., Jarvis, D., Patel, V., Higgerson, R., Christie, L., Typpo, K., Deschenes, J., Kirby, A., Uhl, T., Rehder, K., Cheifetz, I., Wrenn, S., Kypuros, K., Ackerman, K., Maffei, F., Bloomquist, G., Rizkalla, N., Kimura, D., Shah, S., Tigges, C., Su, F., Barlow, C., Michelson, K., Wolfe, K., Goodman, D., Campbell, L., Sorce, L., Bysani, K., Monjure, T., Evans, M., Totapally, B., Chegondi, M., Rodriguez, C., Frazier, J., Steele, L., Viteri, S., Costarino, A., Thomas, N., Spear, D., Hirshberg, E., Lilley, J., Rowan, C., Rider, C., Kane, J., Zimmerman, J., Greeley, C., Lin, J., Jacobs, R., Parker, M., Culver, K., Loftis, L., Jaimon, N., Goldsworthy, M., Diliberto, M., Alen, C., Gessouroun, M., Sapru, A., Lang, T., Alkhouli, M., Kamath, S., Friel, D., Daufeldt, J., Hsing, D., Carlo, C., Pon, S., Scimeme, J., Shaheen, A., Hassinger, A., Qiao, H., Giuliano, J., Tala, J., Vinciguerra, D., Fernandez, A., Carrero, R., Hoyos, P., Jaramillo, J., Posada, A., Izquiierdo, L., Pineres Olave, B. E., Donado, J., Dalmazzo, R., Rendich, S., Palma, L., Lapadula, M., Acuna, C., Cruces, P., De Clety, S. Clement, Dujardin, M., Berghe, C., Renard, S., Zurek, J., Steinherr, H., Mougkou, K., Critselis, E., Di Nardo, M., Picardo, S., Tortora, F., Rossetti, E., Fragasso, T., Cogo, Paola, Netto, R., Dagys, A., Gurskis, V., Kevalas, R., Neeleman, C., Lemson, J., Luijten, C., Wojciech, K., Pagowska Klimek, I., Szczepanska, M., Karpe, J., Nunes, P., Almeida, H., Rios, J., Vieira, M., Garcia Iniguez, J. P., Revilla, P., Urbano, J., Lopez Herce, J., Bustinza, A., Cuesta, A., Hofheinz, S., Rodriguez Nunez, A., Sanagustin, S., Gonzalez, E., Riaza, M., Piaya, R., Soler, P., Esteban, E., Laraudogoitia, J., Monge, C., Herrera, V., Granados, J., Gonzalez, C., Koroglu, T., Ozcelik, E., Baines, P., Plunkett, A., Davis, P., George, S., Tibby, S., Harris, J., Agbeko, R., Lampitt, R., Brierley, J., Peters, M., Jones, A., Dominguez, T., Thiruchelvam, T., Deep, A., Ridley, L., Bowen, W., Levin, R., Macleod, I., Gray, M., Hemat, N., Alexander, J., Ali, S., Pappachan, J., Mccorkell, J., Fortune, P., Macdonald, M., Hudnott, P., Suyun, Q., Singhi, S., Nallasamy, K., Lodha, R., Shime, N., Tabata, Y., Saito, O., Ikeyama, T., Kawasaki, T., Lum, L., Abidin, A., Kee, S., Tang, S., Jalil, R., Guan, Y., Yao, L., Lin, K., Ong, J., Salloo, A., Doedens, L., Mathivha, L., Reubenson, G., Moaisi, S., Pentz, A., Green, R., Schibler, A., Erickson, S., Mceneiry, J., Long, D., Dorofaeff, T., Coulthard, M., Millar, J., Delzoppo, C., Williams, G., Morritt, M., Watts, N., Beca, J., Sherring, C., and Bushell, T.

Subjects
Male, medicine.medical_specialty, Adolescent, Cross-sectional study, Multiple Organ Failure, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Prevalence, children, epidemiology, multiple organ dysfunction syndrome, severe sepsis, Pediatrics, Perinatology and Child Health, Critical Care and Intensive Care Medicine, 030204 cardiovascular system & hematology, Global Health, Intensive Care Units, Pediatric, Pediatrics, Article, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Epidemiology, medicine, Humans, Hospital Mortality, Prospective Studies, 030212 general & internal medicine, Child, Intensive care medicine, Prospective cohort study, Septic shock, business.industry, Infant, Newborn, Infant, Perinatology and Child Health, Prognosis, medicine.disease, Clinical trial, Cross-Sectional Studies, Phenotype, Child, Preschool, Disease Progression, Female, Multiple organ dysfunction syndrome, business
Abstract

Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.Objectives: To describe the epidemiology, morbidity, and mortality of new or progressive multiple organ dysfunction syndrome in children with severe sepsis. Design: Secondary analysis of a prospective, cross-sectional, point prevalence study. Setting: International, multicenter PICUs. Patients: Pediatric patients with severe sepsis identified on five separate days over a 1-year period. Interventions: None. Measurements and Main Results: Of 567 patients from 128 PICUs in 26 countries enrolled, 384 (68%) developed multiple organ dysfunction syndrome within 7 days of severe sepsis recognition. Three hundred twenty-seven had multiple organ dysfunction syndrome on the day of sepsis recognition. Ninety-one of these patients developed progressive multiple organ dysfunction syndrome, whereas an additional 57 patients subsequently developed new multiple organ dysfunction syndrome, yielding a total proportion with severe sepsis-associated new or progressive multiple organ dysfunction syndrome of 26%. Hospital mortality in patients with progressive multiple organ dysfunction syndrome was 51% compared with patients with new multiple organ dysfunction syndrome (28%) and those with single-organ dysfunction without multiple organ dysfunction syndrome (10%) (p < 0.001). Survivors of new or progressive multiple organ dysfunction syndrome also had a higher frequency of moderate to severe disability defined as a Pediatric Overall Performance Category score of greater than or equal to 3 and an increase of greater than or equal to 1 from baseline: 22% versus 29% versus 11% for progressive, new, and no multiple organ dysfunction syndrome, respectively (p < 0.001). Conclusions: Development of new or progressive multiple organ dysfunction syndrome is common (26%) in severe sepsis and is associated with a higher risk of morbidity and mortality than severe sepsis without new or progressive multiple organ dysfunction syndrome. Our data support the use of new or progressive multiple organ dysfunction syndrome as an important outcome in trials of pediatric severe sepsis although efforts are needed to validate whether reducing new or progressive multiple organ dysfunction syndrome leads to improvements in more definitive morbidity and mortality endpoints.

Published
2017

3. Comparison of Pediatric Severe Sepsis Managed in U.S. and European ICUs

Author

Giuliano, John S, Markovitz, Barry P., Brierley, Joe, Levin, Richard, Williams, Gary, Lum, Lucy Chai See, Dorofaeff, Tavey, Cruces, Pablo, Bush, Jenny L., Keele, Luke, Nadkarni, Vinay M., Thomas, Neal J., Fitzgerald, Julie C., Weiss, Scott L., Fontela, P., Tucci, M., Dumistrascu, M., Skippen, P., Krahn, G., Bezares, E., Puig, G., Puig Ramos, A., Garcia, R., Villar, M., Bigham, M., Polanski, T., Latifi, S., Giebner, D., Anthony, H., Hume, J., Galster, A., Linnerud, L., Sanders, R., Hefley, G., Madden, K., Thompson, A., Shein, S., Gertz, S., Han, Y., Williams, T., Hughes Schalk, A., Chandler, H., Orioles, A., Zielinski, E., Doucette, A., Zebuhr, C., Wilson, T., Dimitriades, C., Ascani, J., Layburn, S., Valley, S., Markowitz, B., Terry, J., Morzov, R., Mcinnes, A., Mcarthur, J., Woods, K., Murkowski, K., Spaeder, M., Sharron, M., Wheeler, D., Beckman, E., Frank, E., Howard, K., Carroll, C., Nett, S., Jarvis, D., Patel, V., Higgerson, R., Christie, L., Typpo, K., Deschenes, J., Kirby, A., Uhl, T., Rehder, K., Cheifetz, I., Wrenn, S., Kypuros, K., Ackerman, K., Maffei, F., Bloomquist, G., Rizkalla, N., Kimura, D., Shah, S., Tigges, C., Su, F., Barlow, C., Michelson, K., Wolfe, K., Goodman, D., Campbell, L., Sorce, L., Bysani, K., Monjure, T., Evans, M., Totapally, B., Chegondi, M., Rodriguez, C., Frazier, J., Steele, L., Viteri, S., Costarino, A., Thomas, N., Spear, D., Hirshberg, E., Lilley, J., Rowan, C., Rider, C., Kane, J., Zimmerman, J., Greeley, C., Lin, J., Jacobs, R., Parker, M., Culver, K., Loftis, L., Jaimon, N., Goldsworthy, M., Fitzgerald, J., Weiss, S., Nadkarni, V., Bush, J., Diliberto, M., Alen, C., Gessouroun, M., Sapru, A., Lang, T., Alkhouli, M., Kamath, S., Friel, D., Daufeldt, J., Hsing, D., Carlo, C., Pon, S., Scimeme, J., Shaheen, A., Hassinger, A., Qiao, H., Giuliano, J., Tala, J., Vinciguerra, D., Fernandez, A., Carrero, R., Hoyos, P., Jaramillo, J., Posada, A., Izquiierdo, L., Piñeres Olave, B. E., Donado, J., Dalmazzo, R., Rendich, S., Palma, L., Lapadula, M., Acuna, C., Cruces, P., Clement De Clety, S., Dujardin, M., Berghe, C., Renard, S., Zurek, J., Steinherr, H., Mougkou, K., Critselis, E., Di Nardo, M., Picardo, S., Tortora, F., Rossetti, E., Fragasso, T., Cogo, Paola, Netto, R., Dagys, A., Gurskis, V., Kevalas, R., Neeleman, C., Lemson, J., Luijten, C., Wojciech, K., Pagowska Klimek, I., Szczepanska, M., Karpe, J., Nunes, P., Almeida, H., Rios, J., Vieira, M., Revilla, P., Urbano, J., Lopez Herce, J., Bustinza, A., Cuesta, A., Hofheinz, S., Rodriguez Nunez, A., Sanagustin, S., Gonzalez, E., Riaza, M., Piaya, R., Soler, P., Esteban, E., Laraudogoitia, J., Monge, C., Herrera, V., Granados, J., Gonzalez, C., Koroglu, T., Ozcelik, E., Baines, P., Plunkett, A., Davis, P., George, S., Tibby, S., Harris, J., Agbeko, R., Lampitt, R., Brierley, J., Peters, M., Jones, A., Dominguez, T., Thiruchelvam, T., Deep, A., Ridley, L., Bowen, W., Levin, R., Macleod, I., Gray, M., Hemat, N., Alexander, J., Ali, S., Pappachan, J., Mccorkell, J., Fortune, P., Macdonald, M., Hudnott, P., Suyun, Q., Singhi, S., Nallasamy, K., Lodha, R., Shime, N., Tabata, Y., Saito, O., Ikeyama, T., Kawasaki, T., Lum, L., Abidin, A., Kee, S., Tang, S., Jalil, R., Guan, Y., Yao, L., Lin, K., Ong, J., Salloo, A., Doedens, L., Mathivha, L., Reubenson, G., Moaisi, S., Pentz, A., Green, R., Schibler, A., Erickson, S., Mceneiry, J., Long, D., Dorofaeff, T., Coulthard, M., Millar, J., Delzoppo, C., Williams, G., Morritt, M., Watts, N., Beca, J., Sherring, C., and Bushell, T.

Subjects
Male, Pediatrics, Cross-sectional study, shock, Critical Care and Intensive Care Medicine, Severity of Illness Index, 0302 clinical medicine, Prevalence, Hospital Mortality, Prospective Studies, 030212 general & internal medicine, Practice Patterns, Physicians', Child, Prospective cohort study, Pediatric intensive care unit, Perinatology and Child Health, Europe, Treatment Outcome, Child, Preschool, outcome, children, management, pediatric intensive care unit, Pediatrics, Perinatology and Child Health, Female, medicine.symptom, medicine.medical_specialty, Adolescent, Critical Care, Intensive Care Units, Pediatric, Sepsis, 03 medical and health sciences, Intensive care, Severity of illness, medicine, Humans, Healthcare Disparities, business.industry, Organ dysfunction, Infant, Newborn, Infant, 030208 emergency & critical care medicine, Health Status Disparities, medicine.disease, United States, Clinical trial, Cross-Sectional Studies, Multivariate Analysis, Emergency medicine, business
Abstract

Copyright © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.Objectives: Pediatric severe sepsis remains a significant global health problem without new therapies despite many multicenter clinical trials. We compared children managed with severe sepsis in European and U.S. PICUs to identify geographic variation, which may improve the design of future international studies. Design: We conducted a secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies study. Data about PICU characteristics, patient demographics, therapies, and outcomes were compared. Multivariable regression models were used to determine adjusted differences in morbidity and mortality. Setting: European and U.S. PICUs. Patients: Children with severe sepsis managed in European and U.S. PICUs enrolled in the Sepsis PRevalence, OUtcomes, and Therapies study. Interventions: None. Measurements and Main Results: European PICUs had fewer beds (median, 11 vs 24; p < 0.001). European patients were younger (median, 1 vs 6 yr; p < 0.001), had higher severity of illness (median Pediatric Index of Mortality-3, 5.0 vs 3.8; p = 0.02), and were more often admitted from the ward (37% vs 24%). Invasive mechanical ventilation, central venous access, and vasoactive infusions were used more frequently in European patients (85% vs 68%, p = 0.002; 91% vs 82%, p = 0.05; and 71% vs 50%; p < 0.001, respectively). Raw morbidity and mortality outcomes were worse for European compared with U.S. patients, but after adjusting for patient characteristics, there were no significant differences in mortality, multiple organ dysfunction, disability at discharge, length of stay, or ventilator/vasoactive-free days. Conclusions: Children with severe sepsis admitted to European PICUs have higher severity of illness, are more likely to be admitted from hospital wards, and receive more intensive care therapies than in the United States. The lack of significant differences in morbidity and mortality after adjusting for patient characteristics suggests that the approach to care between regions, perhaps related to PICU bed availability, needs to be considered in the design of future international clinical trials in pediatric severe sepsis.

Published
2016

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